Lecture Slides Presented at SIMS by Medical Unit SIMS Hospital

1. Bleeding and clotting disorder
Dr Nighat majeed
Assistant professor
Medical unit 11
SIMS/SHL Lahore

2. Bleeding and clotting disorder
• Bleeding is a breakdown in hemostasis.

3. Normal physiology of
Hemostasis
• Vascular factors
• Platelet factors
• Plasma factors

5. Vascular Factors
• Local vasoconstriction
• Vessel wall injury triggers the attachment and
activation of platelets and production of fibrin;
platelets and fibrin combine to form a clot.

6. Platelet Factors
Preventing platelet stasis and dilating intact
blood vessels.
• . Endothelial cell nitric oxide.
• Prostacyclin
These mediators are no longer produced when
the vascular endothelium is disrupted.
• After vascular injury initial platelet adhesion is to
von Willebrand's factor (VWF), previously
secreted by endothelial cells into the
subendothelium.(binds to 1b/1X).

7. Platelet Factors
During activation
platelets release
• Adenosin diphosphate (ADP).
• Biochemical changes
• Arachidonic acid is converted to thromboxane A2
;
this reaction requires cyclooxygenase.

8. Platelet Factors
• ADP, thromboxane A2
, and other mediators
promotes platelet aggregation and activate them.
• Another receptor is assembled on the platelet
surface membrane from glycoproteins IIb and IIIa.
Fibrinogen binds to the glycoprotein IIb-IIIa
complexes of adjacent platelets, connecting them.

9. Platelet Factors
• Platelets provide surfaces for the assembly and
activation of coagulation complexes and the
generation of thrombin.
• Thrombin converts fibrinogen to fibrin.
• Fibrin strands bind aggregated platelets to help
secure the platelet-fibrin hemostatic plug.

10. Plasma Factors
• Plasma coagulation factors interact to
produce thrombin, which converts
fibrinogen to fibrin.

11. Plasma Factors
The blood clothing system or coagulation pathway,
like the complement system, is a proteolytic
cascade.
The ultimate goal of the pathway is to produce
thrombin, which can then convert soluble
fibrinogen into fibrin, which forms a clot.
The generation of thrombin,
1-The intrinsic pathway. (generation of factor X).
2-Extrinsic pathways (generation of factor X).
3-Final common pathway which results in
thrombin formation.

12. Plasma Factors
Intrinsic pathway
• Factor XII, high mol wt kininogen, prekallikrein,
and activated factor XI (factor XIa) produce factor
IXa from factor IX. Factor IXa then combines
with factor VIIIa and procoagulant phospholipid
(present on the surface of activated platelets and
tissue cells) to form a complex that activates factor
X.

13. Extrinsic pathway
• There are two components unique to the
extrinsic pathway, tissue factor or factor III,
and factor VII.

14. Plasma Factors
• People with hereditary deficiencies of factor XII,
high mol wt kininogen, or prekallikrein have no
bleeding abnormality.
• People with hereditary factor XI deficiency have
a mild to moderate bleeding disorder. In vivo,
factor XI (an intrinsic pathway factor) is
activated when a small amount of thrombin is
generated.

15. Plasma Factors
• Activation of the intrinsic or extrinsic pathway
activates the common pathway, resulting in
formation of the fibrin clot.
• Three steps are involved:
• 1- A prothrombin activator is produced on the
surface of activated platelets and tissue cells. The
activator is a complex of an enzyme, factor Xa, and
2 cofactors, factor Va and procoagulant
phospholipid.
• 2- The prothrombin activator cleaves prothrombin
into thrombin and another fragment.
• 3 Thrombin induces the generation of fibrin
polymers from fibrinogen.

16. Plasma Factors
• Thrombin also activates factor XIII, an enzyme
that catalyzes formation of stronger bonds
between fibrin molecules, as well as factor VIII
and factor XI.
• Ca ions are needed in most thrombin-generating
reactions (Ca-chelating agents (e.g., citrate,
ethylenediaminetetraacetic acid) are used in vitro
as anticoagulants).

17. Extrinsic pathway
•

18. .
Pathways in blood coagulation.Extrinsic
pathway

19. Fibrinolytic pathway
•
• 2-Ehlers danlos syndrome.
• 3-Hereditary haemorragic talengiectasia.

20. Bleeding disorders (classification)
Defects of blood vessels
• 1-Vascular purpura.
• Meningococcal infection.
• Septicemia.
• Henoch schonlein purpura.
• Uremia.
• Scurvy.

21. Bleeding disorders (classification)
• Platelet disorders.
• Thrombocytopenia.
Idiopathic
Secondary
• Thrombocythamia
• Thromboasthenia

22. Bleeding disorders (classification)
Clotting disorders
Hereditary
• Hemophilia.
• Christmas disease.
• Von willebrand disease.
Acquired
• Vitamin K deficiency.
• Oral anticoagulant therapy.
• Advanced liver disease.

23. Platelet disorders
(thrombocytopenia)
Causes of thrombocytopenia
• Bone marrow disorders
• Aplastic anemia
• Hematologic malignancies
• Myelodysplasia
• Megaloblastic anemia
• Chronic alcoholism

24. Platelet disorders
(thrombocytopenia)
Nonmarrow disorders
• Immune disorders
• Idiopathic thrombocytopenic purpura
• Drug-induced
• Secondary (CLL, SLE)
• Posttransfusion purpura

25. Platelet disorders
(thrombocytopenia)
• Hypersplenism.
• Disseminated intravascular coagulation.
• Thrombotic thrombocytopenic purpura.
• Hemolytic-uremia syndrome.
• Sepsis.
• Hemangiomas.
• Viral infections, AIDS.
• Liver failure.
• chronic lymphocytic leukemia; systemic lupus
erythematosus.

26. Platelet disorders
Qualitative platelet disorders
• Congenital.
• Glanzmann's thrombasthenia.
• Bernard–Soulier syndrome.
• Storage pool disease.

27. Platelet disorders
• Acquired
• Myeloproliferative disorders.
• Uremia.
• Drugs: aspirin, anti-inflammatory agents.
• Autoantibody.
• Paraproteins.
• Acquired storage pool disease.
• Fibrin degradation products.
• von Willebrand's disease.

28. Diagnostic approach (History)
• Weather the patient has experienced abnormal
bleeding or bruising in the past.
• The site, extent and duration of previous
hemorrhagic phenomenon.
• Response to treatment.
• History of bleeding with minor
injuries,lacerations, circumcision, tooth extraction,
appendectomy, menses, and umbilical cord, as
well as delayed bleeding and keloid formation.

29. Diagnostic approach (History)
• History of use of medicines that interfere with
hemostasis, e:g oral contraceptives, aspirin,
NSAIDS, antibiotics, sodium warfarin or heparin.
• A positive family history of bleeding suggests the
presence of sex linked or autosomal dominant
disorders.
• Vascular wall defect may be congenital.

30. Diagnostic approach (History)
• In platelet and capillary dysfunction there is
superficial bleeding from skin and mucous
membrane.
• In coagulation defect bleeding occurs deep into
the tissues and surgery is not possible without
prior treatment of defect.

31. Diagnostic approach (History)
• Patient presents with bleeding from various sites.
• Common presentations are bleeding from gums,
epistaxis, hematemesis, hemoptysis, haematuria,
menorragia.
• History of neoplasia, uremia, liver disease.

32. Characteristics of bleeding in
hemorrhagic disorders
Petechia
• Punctate;about 1mm in diameter.on extremities
usually absent over pressure points,occur due to
vascular defect or platelet abnormality.

33. Characteristics of bleeding in
hemorrhagic disorders
Purpura
1mm to 1cm, generally truncal, occasionally
extremities.it is usually due to vascular
abnormalities.

34. Characteristics of bleeding in
hemorrhagic disorders
Ecchymosis
• Larger bleed with local extravasation.It occurs on
soft tissues and joints.it occur due to factor
deficiency or open blood vessel.

35. Characteristics of bleeding in
hemorrhagic disorders
Generalized
• Diffuse or generalized ecchymosis, occurs on
larger areas, mucous membranes and wounds.
• Usually associated with disseminated intravascular
clotting or primary fibrinolysis.

36. Diagnostic approach (History)
• Hereditary hemorrhagic telangiectasia
A congenital vessel wall abnormalities, such as,
defect in a gene coding for endoglin and TGF-ß
which are angiogenic cytokines concerned with
vascular modeling leading to formation of
telangiectasias or small aneurysms.
Patient presents with recurrent bleed(epistaxis), or
with iron deficiency due to gastrointestinal bleed.

37. Diagnostic approach (History)
• Ehler-Danlos disease a congenital disorder of
collagen synthesis ecchymoses occur commonly
in skin because capillaries are poorly supported by
subcutaneous collagen.
• Vasculitis an inflammation of arterial wall may be
acquired.

38. Diagnostic approach (History)
Platelet disorders
• Spontaneous bleeding occur if platelet count falls
below 30*109/l.
• Purpura and spontaneous bruising are
characteristic.
• There may be oral, nasal,gastrointestinal or
genitourinary bleeding.
• Severe thrombocytopaenia cause optic fundal
hemorrhage or intracranial bleed.

39. Diagnostic approach (History)
Drugs inhibiting platelet functions
NSAIDS
Aspirin
Indomethacin
Antibiotics
Penicillins
Dextran
Heparin
B blockers
Phenylbutazone
Sulfinpyrazone
cephalosporins

40. Diagnostic approach (History)
Coagulation disorders
Hazards of coagulation disorders is increased with
• surgical procedures.
• Cardiopulmonary bypass procedures.
• hypothermia.
• prostate surgery, cardiovascular surgery.
• trauma and massive bleeding without replacement
of clotting factors.

41. Laboratory tests of bleeding
patient
• Prothrombin time.
• Activated partial thromboplastin time.
• Platelet count.
• Fibrinogen level.
• Fibrin split products or D-dimer or both.
• Bleeding time.
• Hemoglobin or haematocrit.
• Peripheral blood smear.
• Specific factor assay.
• Assays for inhibitors and antibodies.
• Platelet aggregation and antibody studies.

42. Laboratory tests of bleeding
patient
Prothrombin time
• The prothrombin time (PT) and its derived
measures of prothrombin ratio (PR) and
international normalized ratio (INR) are measures
of the extrinsic pathway of coagulation.
• PT measures factors II, V, VII, X and fibrinogen.

43. Prothrombin time
Prothrombin time time is prolonged in,
• Vitamin K deficiency.
• Disseminated intravascular coagulation.
• Haemophilia.PT is unaffected.
• Heparin overdose.

44. Prothrombin time
• The INR is the ratio of a patient's prothrombin
time to a normal (control) sample, raised to the
power of the ISI value for the analytical system
used.
Pttest
INR = ( --------- )
Ptnormal

45. Prothrombin time
• The reference range for prothrombin time is
usually around 12–15 seconds; the normal
range for the INR is 0.8– 1.2.

46. • International normalized ratio
• The result (in seconds) for a Prothrombin time performed on a normal
individual will vary depending on what type of analytical system it is
performed on. This is due to the differences between different batches of
manufacturer's tissue factor used in the reagent to perform the test. The INR
was devised to standardize the results.
• Each manufacturer assigns an ISI value (International Sensitivity Index) for
any tissue factor they manufacture. The ISI value indicates how a particular
batch of tissue factor compares to an internationally standardized sample. The
ISI is usually between 1.0 and 2.0.
• The INR is the ratio of a patient's prothrombin time to a normal (control)
sample, raised to the power of the ISI value for the analytical system used.

47. Laboratory tests of bleeding
patient
Activated partial thromboplastin time
• The partial thromboplastin time (PTT) or activated
partial thromboplastin time (aPTT or APTT) is a
measure of the efficacy of both the "intrinsic" and
the common coagulation pathways.
• Apart from detecting abnormalities in blood
clotting, it is also used to monitor the treatment
effects with heparin, a major anticoagulant. It is
used in conjunction with the prothrombin time
(PT) which measures the extrinsic pathway.

48. Laboratory tests of bleeding
patient
Partial thromboplastin time is prolonged in,
• Vitamin K deficiency.
• Disseminated intravascular coagulation.
• Haemophilia.
• Heparin overdose.

49. Bleeding time
• Bleeding time is a medical test done on someone
to assess their platelet function.
• It involves cutting the underside of the subject's
forearm, in an area where there is no hair or
visible veins. The cut is of a standardized width
and depth, and is done quickly by an automatic
device.
• A normal value is less than 9 and a half minutes.

50. Laboratory tests of bleeding
patient
Vascular defects and von willebrand,s disease
• Bleeding time is prolonged.
• Ristocetin cofactor assay of VWF antigen.
• VWF antigen.
• VWF multimeric assay.

51. Laboratory tests of bleeding
patient
Platelet defects
Direct examination of stained smear.
Platelet count.
Bleeding time.
Platelet adhesion.
Platelet aggregation.
Assay for platelet factor 3.
Clot retraction.

52. Laboratory tests of bleeding
patient
Factor deficiencies
Factor V111 deficiency classic Hemophilia.
• Factor V111 assay.
• APTT.
Factor 1X deficiency in Christmas disease.
• Factor 1X assay.
• APTT.